Stroke is the third leading cause of mortality and the leading cause of severe disability worldwide. It is a complex disease that results from many different pathologic conditions including atherosclerosis and hypertension and is therefore affected by multiple genetic and environmental factors. Understanding the genetic basis of stroke will allow us to gain a deeper understanding of the mechanisms behind its pathogenesis. As a complex disease trait, the genetic basis of stroke susceptibility can be studied by using quantitative trait loci analysis to identify regions of DNA that are associated with it. In this proposal, we aim to study the susceptibility to cerebral infarction in the presence of focal cerebral ischemia in mice via an integrative strain survey. We hypothesize that susceptibility to cerebral infarction in the presence of ischemia vary among inbred strains of mice and that this phenotypic variability across strains has a genetic basis. We will perform in silico QTL mapping (haplotype association mapping) for inbred strain phenotypes to identify potential chromosomal regions with stroke susceptibility genes. We will integrate the QTL results with that of microarray gene expression analysis and other bioinformatics tools to narrow down the QTL regions for selection of candidate genes causing stroke susceptibility. The single gene analysis will be extended to incorporate probabilistic gene networks. The candidate genes which affect the vulnerability to stroke as predicted by the QTL mapping can be applied to human studies and ultimately lead to therapeutic and predictive tools for cerebral protection in patients with a variety of cerebrovascular diseases. PUBLIC HEALTH RELEVANCE: Stroke is a major public health burden. This project uses a mouse model of stroke to examine the genetic basis of stroke susceptibility. This will be accomplished via computational and bioinformatics tools together with the emerging genetics resources.